An Update on the Hereditary Spastic Paraplegias: New Genes and New Disease Models

Abstract

Aims: The hereditary spastic paraplegias (HSPs) are a heterogeneous group of disorders characterized by spasticity in the lower limbs. We provide an overview of HSP with an emphasis on recent developments.

Methods: A PubMed search using the term "hereditary spastic paraplegia" and "hereditary spastic paraparesis" was conducted for a period from January 2012 to January 2015. We discuss and critique the major studies in the field over this 36-month period.

Results: A total of 346 publications were identified, of which 47 were selected for review. We provide an update of the common forms of HSP and include patient videos. We also discuss how next-generation sequencing (NGS) has led to the accelerated discovery of new HSP genes, including B4GALNT1,DDHD1, C19orf12,GBA2,TECPR2,DDHD2, C12orf65,REEP2, and IBA57. Moreover, a single study alone identified 18 previously unknown putative HSP genes and created a model for the protein interactions of HSP, called the "HSPome." Many of the newly reported genes cause rare, complicated, autosomal recessive forms of HSP. NGS also has important clinical applications by facilitating the molecular diagnosis of HSP. Furthermore, common genetic forms of HSP have been studied using new disease models, such as neurons derived from induced pluripotent stem cells. These models have been used to elucidate important disease mechanisms and have served as platforms to screen for candidate drug compounds.

Conclusion: The field of HSP research has been progressing at a rapid pace. The challenge remains in translating these advances into new targeted disease therapies.

Keywords: hereditary spastic paraplegia; next generation sequencing; review.

Figure 1

Muscle biopsy from a patient with SPG7 (p.A510V, p.S576W mutations, as previously reported37), demonstrating an abnormal number of cytochrome oxidase negative/succinate dehydrogenase positive fibres consistent with a mitochondrial cytopathy.

Figure 2

Number of HSP genes discovered per calendar year. The most common HSP genes are indicated (blue arrows). Whole‐exome sequencing has been used for gene discovery in HSP since 2011 (green arrow), resulting in a marked increase in the rate of new genes being identified.

Figure 3

Genetic testing strategies in HSP. MLPA, multiplex ligation probe amplification.